title: High-throughput profiling of alpha interferon- and interleukin-28B-regulated microRNAs and identification of let-7s with anti-hepatitis C virus activity by targeting IGF2BP1.
abstract: Hepatitis C virus (HCV) infection is a major cause of severe liver disease. Interferon (IFN)/ribavirin treatment remains the standard therapeutic regimen for HCV infection in most countries. IFN-stimulated genes are believed to contribute to antiviral effects. However, emerging evidence suggests that microRNAs (miRNAs), a class of noncoding small RNAs, are involved in the control of viral infection. Here, we systematically profiled the hepatocyte expression of a set of 750 miRNAs in response to alpha interferon (IFN-α) and interleukin-28B (IL-28B) treatments. The anti-HCV activity of differentially expressed miRNAs was evaluated using cell culture-derived HCV in vitro. The results demonstrate that let-7b had a significant anti-HCV effect by inhibiting HCV replication and viral protein translation in human hepatoma cells. In particular, we show that the inhibition of let-7b attenuated the anti-HCV effects of IFN-α and IL-28B. Furthermore, we show that the host factor insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is a target of let-7b. IGF2BP1 was required for HCV replication, and its expression was downregulated by IFN-α and IL-28B. Deletion of the wild-type seed region of let-7b abolished its antiviral activity. Finally, we demonstrate that other let-7 family miRNAs were able to inhibit HCV and to suppress IGF2BP1 expression. In conclusion, we provide an example of a host miRNA regulated by type I and type III IFNs that inhibits HCV replication and infectivity by targeting host targets. These results highlight the important role of miRNAs in the host antiviral immune response and provide a novel candidate for anti-HCV therapy.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.forename: Youhui
authors.initials: Y
authors.lastname: Si
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Niu
authors.forename: Xiuying
authors.initials: X
authors.lastname: Liu
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D015536:Down-Regulation; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology / Q000628:therapy; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D057166:High-Throughput Screening Assays; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C406144:IGF2BP1 protein, human; C487931:mirnlet7 microRNA, human